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This Article Full Text (PDF) All Versions of this Article: jimmunol.0802665v1 183/11/7031    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Panchanathan, R. Articles by Choubey, D. PubMed PubMed Citation Articles by Panchanathan, R. Articles by Choubey, D.

Female and Male Sex Hormones Differentially Regulate Expression of Ifi202, an Interferon-Inducible Lupus Susceptibility Gene within the Nba2 Interval¹

Ravichandran Panchanathan,^* Hui Shen,^* Melanie Gubbels Bupp,² Karen A. Gould, and Divaker Choubey^3*

*Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267; Division of Clinical Immunology and Human Medical Genetics, University of Colorado Health Sciences Center, Denver, CO 80262; and Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198

Increased expression of IFN-inducible Ifi202 gene in certain strains of female mice is associated with susceptibility to systemic lupus erythematosus (SLE). Although, the development of SLE is known to have a strong sex bias, the molecular mechanisms remain unknown. Here we report that in vivo treatment of orchiectomized (NZB x NZW)F₁ male mice with the female sex hormone 17β-estradiol significantly increased steady-state levels of Ifi202 mRNA in splenic cells, whereas treatment with the male hormone dihydrotestosterone decreased the levels. Moreover, increased expression of Ifi202 in B6.Nba2 B cells and reduced expression in T cells were associated with increased levels of estrogen receptor- (ER) and androgen receptor, respectively. Furthermore, the steady-state levels of Ifi202 mRNA were higher in splenic cells from C57BL/6, B6.Nba2, NZB, and (NZB x NZW)F₁ female mice as compared with males. 17β-estradiol treatment of B cells and WT276 cells increased Ifi202 mRNA levels, whereas treatment with dihydrotestosterone decreased the levels. Interestingly, overexpression of ER in WT276 cells increased the expression of Ifi202 and stimulated the activity of the 202-luc-reporter through the c-Jun/AP-1 DNA-binding site. Accordingly, ER preferentially associated with the regulatory region of the Ifi202 gene in female B6.Nba2 B cells than in males. Furthermore, Ifi202 mRNA levels were detectable in splenic cells of wild-type (Esr1^+/+), but not null (Esr1^–/–), (NZB x NZW)F₁ female mice. Collectively, our observations demonstrate that the female and male sex hormones differentially regulate the expression of Ifi202, thus providing support for the role of Ifi202 in sex bias in SLE.

Correspondence: ³ Address correspondence and reprint requests to Dr. Divaker Choubey, Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P.O. Box 670056, Cincinnati, OH 45267. E-mail address: Divaker.choubey{at}uc.edu

¹ This work was supported by National Institutes of Health Grant R01 AI066261 to D.C. A Predoctoral Award (no. 0315287Z) from the American Heart Association supported M.G.B.

² Current address: Roche Palo Alto, Palo Alto, CA 94304.